Organic Compounds

ABSTRACT

The present invention relates to compounds selected from the group consisting of 14-0-[((Mono- or dialkylamino)-cycloalkylsulfanyl- or -cycloalkyl-oxy)-acetyl, -thioacetyl or -imino-oxy]-mutilins, 14-O-[((Cycloalkyl- or heterocyclylamino)-cy-cloalkylsulfanyl- or -cycloalkyl-oxy)-acetyl, -thioaceyl or -imino-oxy]-mutilins, 14-O-[((Heterocyc-N-yl-cycloalkyl)-sulfanyl- or -oxy)-acetyl, -thioacetyl or -imino-oxy]-mutilins, 14-O-[(((Mono- or dialkylamino)-cycloalkyl)-alkylsulfanyl- or -alkyl-oxy)-acetyl, -thioacetyl or -imino-oxy]-mutilins, 14-O-[(((Cycloalkyl- or heterocyclylamino)-cycloalkyl)-alkylsulfanyl- or -alkyl-oxy)-acetyl, -thioacetyl or -imino-oxy]-mutilins, and 14-O-[((Heterocyc-N-yl-cycloalkyl)-alkylsulfanyl- or -alkyl-oxy)-acetyl, -thioacetyl or -imino-oxy]-mutilins, and their use as pharmaceuticals.

The present invention relates to organic compounds, such aspleuromutilins.

Pleuromutilin, a compound of formula A

is a naturally occurring antibiotic, e.g. produced by the basidomycetesPleurotus mutilus and P. passeckerianus, see e.g. The Merck Index, 13thedition, item 7617.

A number of further pleuromutilins having the principle ring structureof pleuromutilin and being substituted at the hydroxy group have beendeveloped, e.g. as antimicrobials.

We have now found pleuromutilins with interesting activity.

A pleuromutilin provided by the present invention includes apleuromutilin having the basic structural elements of the mutilin ringsystem as set out in formula PLEU

wherein R_(PLEU) is vinyl or ethyl and the dotted line is a bond or isno bond.

The following numbering system is used in the present application:

The dotted line between positions 19 an 20 (and between positions 1 and2) is a bond or is no bond. In a compound of formula A or of formulaPLEU a hydrogen atom in positions 4, 7 and/or 8 of the ring system maybe replaced by deuterium, and if the dotted line between positions 1 and2 is no bond (single bond between positions 1 and 2) the ring system maybe further substituted in positions 1 and/or 2, e.g. by halogen,deuterium or hydroxy. The group —O— in position 14 is furthersubstituted, preferably by a substituted carbonyl group.

In one aspect the present invention provides a compound, i.e. apleuromutilin, selected from the group consisting of

-   14-O-[((Mono- or dialkylamino)-cycloalkylsulfanyl- or    -cycloalkyl-oxy)-acetyl, -thioacetyl or -imino-oxy]-mutilins,-   14-O-[((Cycloalkyl- or heterocyclylamino)-cycloalkylsulfanyl- or    -cycloalkyl-oxy)-acetyl, -thioacetyl or -imino-oxy]-mutilins,-   14-O-[((Heterocyc-N-yl-cycloalkyl)-sulfanyl- or -oxy)-acetyl,    -thioacetyl or -imino-oxy]-mutilins,-   14-O-[(((Mono- or dialkylamino)-cycloalkyl)-alkylsulfanyl- or    -alkyl-oxy)-acetyl, -thioacetyl or -imino-oxy]-mutilins,-   14-O-[(((Cycloalkyl- or    heterocyclylamino)-cycloalkyl)-alkylsulfanyl- or -alkyl-oxy)-acetyl,    -thioacetyl or -imino-oxy]-mutilins, and-   14-O-[((Heterocyc-N-yl-cycloalkyl)-alkylsulfanyl- or    -alkyl-oxy)-acetyl, -thioacetyl or -imino-oxy]-mutilins,    preferably,-   14-O-[((Mono- or dialkylamino)-cycloalkylsulfanyl- or    -cycloalkyl-oxy)-acetyl]-mutilins,-   14-O-[((Cycloalkyl- or heterocyclylamino)-cycloalkylsulfanyl- or    -cycloalkyl-oxy)-acetyl]-mutilins,-   14-O-[((Heterocyc-N-yl-cycloalkyl)-sulfanyl- or    -oxy)-acetyl]-mutilins,-   14-O-[(((Mono- or dialkylamino)-cycloalkyl)-alkylsulfanyl- or    -alkyl-oxy)-acetyl]-mutilins,-   14-O-[(((Cycloalkyl- or    heterocyclylamino)-cycloalkyl)-alkylsulfanyl- or    -alkyl-oxy)-acetyl]-mutilins, and-   14-O-[((Heterocyc-N-yl-cycloalkyl)-alkylsulfanyl- or    -alkyl-oxy)-acetyl]-mutilins, more preferably-   14-O-[((Mono- or dialkylamino)-cycloalkylsulfanyl- or    -cycloalkyl-oxy)-acetyl]-mutilins,-   14-O-[((Cycloalkyl- or heterocyclylamino)-cycloalkylsulfanyl- or    -cycloalkyl-oxy)-acetyl]-mutilins, and-   14-O-[((Heterocyc-N-yl-cycloalkyl)-sulfanyl- or    -oxy)-acetyl]-mutilins.

According to a preferred embodiment of the invention, the compound is a

-   14-O-[((Mono- or dialkylamino)-cycloalkylsulfanyl)-acetyl]-mutilin,-   14-O-[((Cycloalkyl- or    heterocyclylamino)-cycloalkylsulfanyl)-acetyl]-mutilin, or-   14-O-[((Heterocyc-N-yl-cycloalkyl)-sulfanyl)-acetyl]-mutilin.

In the above compounds

-   -   cycloalkyl is (C₃₋₁₂)cycloalkyl, such as (C₄₋₈)cycloalkyl, e.g.        (C₅₋₇)cycloalkyl,    -   heterocyclyl includes a heterocyclic group comprising 3 to 7        ring members, preferably 5 to 6 ring members, and one to four,        preferably 2, heteroatoms selected from N, O and S, preferably        N, O, which heterocyclyl may be anellated with another        ring/system, such as (C₆₋₁₂)aryl, e.g. phenyl,    -   “Heterocyc-N-yl-cycloalkyl” means heterocyclyl comprising 5 to 7        ring members and 1 to 4 heteroatoms selected from N, O and S        which comprises at least one nitrogen heteroatom, which nitrogen        atom is bond to the cycloalkyl, such as morpholin-1-yl,    -   alkyl is preferably (C₁₋₈)alkyl, such as (C₁₋₄)alkyl,    -   alkyl includes unsubstituted alkyl and substituted alkyl, e.g.        unsubstituted alkyl or alkyl substituted by one or more of        -   hydroxy; e.g. one or two,        -   halogen,        -   alkyloxycarbonyl, such as (C₁₋₆)alkyloxycarbonyl; e.g. one,        -   alkylaminocarbonyl, such as (C₁₋₄)alkylaminocarbonyl; e.g.            one,        -   cycloalkyl, e.g. (C₃₋₈)cycloalkyl, e.g. cyclohexyl; e.g.            one,        -   aryl, e.g. (C₆₋₁₈)aryl, e.g. phenyl; e.g. one,        -   heterocyclyl including a heterocyclic group comprising 3 to            7 ring members, preferably 5 to 6 ring members, and one to            four, preferably 2, heteroatoms selected from N, O and S,            preferably N, O, which heterocyclyl may be anellated with            another ring/system, such as (C₆₋₁₈)aryl, e.g. phenyl, such            as imidazolyl, e.g. imidazol-2-yl, benzimidazolyl, e.g.            benzimidazol-2-yl; e.g. one;            with the proviso that, in case of            14-O-[((Heterocyc-N-yl-cycloalkyl)-sulfanyl- or            -oxy)-acetyl, -thioacetyl or -imino-oxy]-mutilins or            14-O-[((Heterocyc-N-yl-cycloalkyl)-alkylsulfanyl- or            -alkyl-oxy)-acetyl, -thioacetyl or -imino-oxy]-mutilins, the            heterocyclyl group is attached to cycloalkyl via a            heterocyclic nitrogen atom.

A preferred compound according to the invention is a compound of generalformula I

whereinR is hydrogen or (C₁₋₈)alkyl,

R₁ is

-   -   cycloalkyl including (C₃₋₁₂)cycloalkyl, such as        (C₄₋₈)cycloalkyl, e.g. (C₅₋₇)cycloalkyl,    -   unsubstituted (C₁₋₈)alkyl, or    -   (C₁₋₈)alkyl substituted by one or more of        -   hydroxy; preferably one or two,        -   halogen,        -   alkyloxycarbonyl, such as (C₁₋₆)alkyloxycarbony; preferably            one,        -   alkylaminocarbonyl, such as (C₁₋₄)alkylaminocarbonyl;            preferably one,        -   (C₃₋₈)cycloalkyl, e.g. cyclohexyl; preferably one,        -   (C₆₋₁₈)aryl, e.g. phenyl; preferably one,        -   heterocyclyl including a heterocyclic group comprising 3 to            7 ring members, preferably 5 to 6 ring members, and 1 to 4,            preferably 2, heteroatoms selected from N, O and S,            preferably N, O, which heterocyclyl may be anellated with            another ring/system, such as (C₆₋₁₈)aryl, e.g. phenyl, such            as imidazolyl, e.g. imidazol-2-yl, benzimidazolyl, e.g.            benzimidazol-2-yl; preferably one,            X is sulphur, oxygen or NR₁₀, wherein R₁₀ is hydrogen or            (C₁₋₈)alkyl;            Y is sulphur or oxygen;            R₂ is hydrogen or one or more substituents, e.g. including            substituents such as conventional in organic, e.g.            (pleuro)mutilin, chemistry, e.g. (C₁₋₄)alkyl, halogen;            R₄ and R₅ independently of each other are hydrogen or            (C₁₋₈)alkyl;            R₃ and R₃′ are hydrogen, deuterium or halogen;            R₆, R₇ and R₈ independently of each other are hydrogen,            halogen or deuterium;            m is a number selected from 0 to 4,            n is a number selected from 0 to 10, and            p is a number selected from 0 to 10;            with the proviso that n plus p are at least 1, and            preferably less than 13, such as 3 to 8, e.g. 3 to 5.

According to a preferred embodiment, in a compound of formula I,

-   -   R and R₁ are as defined above,    -   R₂ is hydrogen or (C₁₋₄)alkyl;    -   R₃ is hydrogen,    -   R₃′ is hydrogen,    -   R₄ is hydrogen,    -   R₅ is hydrogen,    -   R₆ is hydrogen,    -   R₇ is hydrogen,    -   X is oxygen,    -   Y is sulphur,    -   m is a number selected from 0 to 4, more preferably m is 0,    -   n is a number selected from 0 to 8, more preferably from 0 to 7,        such as 2 or 3,    -   p is a number selected from 0 to 8, more preferably from 0 to 7,        such as 1,        with the proviso that n plus p are at least 2, and preferably        less than 9; more preferably n plus p is 3 or 4;        e.g. wherein each single substituent defined may be a preferred        substituent, independently from the other substituents defined.

A further preferred compound of the invention is a compound of formulaI_(p)

such as a compound of formula I_(pp)

wherein R and R₁ are as defined above,R₂ is hydrogen or (C₁₋₄)alkyl, andq is a number selected from 0, 1 and 2.

In formula I_(p) a group —N(RR₁) may be in any position of thecycloalkyl ring system and is preferably in position 3 or in position 4,more preferably in position 3, e.g. as in a compound of formula I_(pp).

According to a further preferred embodiment of the present invention,the compound is selected from the group consisting of

-   14-O-[(3-Diethylamino-cyclohexan-1-yl)-sulfanylacetyl]-mutilin, such    as-   14-O-[(3(R*)-Diethylamino-cyclohexan-1(S*)-yl)-sulfanylacetyl]-mutilin,    and-   14-O-[(3(R*)-Diethylamino-cyclohexan-1(R*)-yl)-sulfanylacetyl]-mutilin;-   14-O-{[(3-Methylamino-cyclopent-1-yl)-sulfanyl]-acetyl}-mutilin,    such as-   14-O-{[(3(R/S)-Methylamino-cyclopent-1(R/S)-yl)-sulfanyl]-acetyl}-mutilin;-   14-O-{[(3-Ethylamino-cyclopent-1-yl)-sulfanyl]-acetyl}-mutilin, such    as-   14-O-{[(3(R/S)-Ethylamino-cyclopent-1(R/S)-yl)-sulfanyl]-acetyl}-mutilin;-   14-O-{[(3-Ethylamino-1-methyl-cyclopent-1-yl)-sulfanyl]-acetyl}-mutilin,    such as-   14-O-{[(3(R/S)-Ethylamino-1-methyl-cyclopent-1(R/S)-yl)-sulfanyl]-acetyl}-mutilin;-   14-O-{[(3-Ethylamino-2-methyl-cyclopent-1-yl)-sulfanyl]-acetyl}-mutilin,    such as-   14-O-{[(3(R/S)-Ethylamino-2-methyl-cyclopent-1(R/S)-yl)-sulfanyl]-acetyl}-mutilin;-   14-O-{[3-Ethylamino-cyclohexanylsulfanyl]-acetyl}-mutilin, such as-   14-O-{[3(S)-Ethylamino-cyclohexan-1(R)-ylsulfanyl]-acetyl}-mutilin,    and-   14-O-{[3(R)-Ethylamino-cyclohexan-1(R)-ylsulfanyl]-acetyl}-mutilin;-   14-O-{[3-(sec-Butylamino)-cyclopent-1-ylsulfanyl]-acetyl}-mutilin,    such as-   14-O-{[3(R/S)-((S)-sec-Butylamino)-cyclopent-1(R/S)-ylsulfanyl]-acetyl}-mutilin,    and-   14-O-{[3(R/S)-((R)-sec-Butylamino)-cyclopent-1(R/S)-ylsulfanyl]-acetyl}-mutilin;-   14-O-[((3-(sec-Butylamino)-cyclohexan-1-yl)-sulfanyl)-acetyl]-mutilin,    such as-   14-O-[((3(S*)-(sec-(R)-Butylamino)-cyclohexan-1(R*)-yl)-sulfanyl)-acetyl]-mutilin,-   14-O-[((3(S*)-(sec-(R)-Butylamino)-cyclohexan-1(S*)-yl)-sulfanyl)-acetyl]-mutilin,-   14-O-[((3(S*)-(sec-(S)-Butylamino)-cyclohexan-1(S*)-yl)-sulfanyl)-acetyl]-mutilin,    and-   14-O-[((3(S*)-(sec-(S)-Butylamino)-cyclohexan-1(R*)-yl)-sulfanyl)-acetyl]-mutilin;-   14-O-[((1-(sec-Butylamino)-cycloheptan-3-yl)-sulfanyl)-acetyl]-mutilin,    such as-   14-O-[((1-((R/S)-(sec-(R)-Butylamino)-cycloheptan-3(R/S)-yl)-sulfanyl)-acetyl]-mutilin;-   14-O-{[3-(2,2,2-Trifluoro-ethylamino)-cyclopent-1-ylsulfanyl]-acetyl}-mutilin,    such as-   14-O-{[3(R/S)-(2,2,2-Trifluoro-ethylamino)-cyclopent-1(R/S)-ylsulfanyl]-acetyl}-mutilin;-   14-O-{[3-(2,2,2-Trifluoro-ethylamino)-cyclohexan-1-ylsulfanyl]-acetyl}-mutilin,    such as-   14-O-{[3(R/S)-(2,2,2-Trifluoro-ethylamino)-cyclohexan-1(R/S)-ylsulfanyl]-acetyl}-mutilin;-   14-O-{[3-(2,2-Difluoro-ethylamino)-cyclohexan-1-ylsulfanyl]-acetyl}-mutilin,    such as-   14-O-{[3(R/S)-(2,2-Difluoro-ethylamino)-cyclohexan-1(R/S)-ylsulfanyl]-acetyl}-mutilin,-   14-O-{[(3-(2-Hydroxy-ethylamino)-cyclopent-1-yl)-sulfanyl]-acetyl}-mutilin,    such as-   14-O-{[(3(R/S)-(2-Hydroxy-ethylamino)-cyclopent-1(R/S)-yl)-sulfanyl]-acetyl}-mutilin;-   14-O-{[3-(2-Hydroxy-propylamino)-cyclopent-1-ylsulfanyl]-acetyl}-mutilin,    such as-   14-O-{[3(R/S)-(2-(S)-Hydroxy-propylamino)-cyclopent-1(R/S)-ylsulfanyl]-acetyl}-mutilin,-   14-O-{[3(R/S)-(2-(R)-Hydroxy-propylamino)-cyclopent-1(R/S)-ylsulfanyl]-acetyl}-mutilin,-   14-O-[((3-(1-Isopropyl-2-hydroxy-ethylamino)-cyclopent-1-yl)-sulfanyl)-acetyl]-mutilin,    such as-   14-O-[((3(R/S)-(1(S)-Isopropyl-2-hydroxy-ethylamino)-cyclopent-1(R/S)-yl)-sulfanyl)-acetyl]-mutilin,-   14-O-[((3-(1-Isopropyl-2-hydroxy-ethylamino)-cyclohexan-1-yl)-sulfanyl)-acetyl]-mutilin,    such as-   14-O-[((3(R/S)-(1(S)-Isopropyl-2-hydroxy-ethylamino)-cyclohexan-1(R/S)-yl)-sulfanyl)-acetyl]-mutilin;-   14-O-{[3-(2-Hydroxy-1-hydroxymethyl-1-methyl-ethylamino)-eyclopent-1-ylsulfanyl]-acetyl}-mutilin,    such as-   14-O-{[3(R/S)-(2-Hydroxy-1-hydroxymethyl-1-methyl-ethylamino)-cyclopent-1(R/S)-ylsulfanyl]-acetyl}-mutilin;-   14-O-{[3-(2-Hydroxy-1,1-bis-hydroxymethyl-ethylamino)-cyclopent-1-ylsulfanyl]-acetyl}-mutilin,    such as-   14-O-{[3(R/S)-(2-Hydroxy-1,1-bis-hydroxymethyl-ethylamino)-cyclopent-1(R/S)-ylsulfanyl]-acetyl}-mutilin;-   14-O-[((3-(Methoxycarbonyl-methylamino)-cylopent-1-yl)-sulfanyl)-acetyl]-mutilin,    such as-   14-O-[((3(R/S)-(Methoxycarbonyl-methylamino)-cyclopent-1(R/S)-yl)-sulfanyl)-acetyl]-mutilin;-   14-O-[((3-(Ethoxycarbonyl-methylamino)-cyclopent-1-yl)-sulfanyl)-acetyl]-mutilin,    such as-   14-O-[((3(R/S)-(Ethoxycarbonyl-methylamino)-cyclopent-1(R/S)-yl)-sulfanyl)-acetyl]-mutilin;-   14-O-[(((3-(Isopropoxycarbonyl-methylamino)-cyclopent-1-yl)-sulfanyl)-acetyl]-mutilin,-   such as-   14-O-[(((3(R/S)-(Isopropoxycarbonyl-methylamino)-cyclopent-1(R/S)-yl)-sulfanyl)-acetyl]-mutilin;-   14-O-{[3-(Methoxypropionyl-2-amino)-cyclopent-1-yl-sulfanyl]-acetyl}-mutilin,    such as-   14-O-{[3(S*)-(Methoxypropionyl-2(S)-amino)-cyclopent-1(R/S)-yl-sulfanyl]-acetyl}-mutilin;-   14-O-{[3-(Isopropoxypropionyl-2-amino)-cyclopent-1-yl-sulfanyl]-acetyl}-mutilin,    such as-   14-O-{[3(R*)-(Isopropoxypropionyl-2(S)-amino)-cyclopent-1(R*)-yl-sulfanyl]-acetyl}-mutilin,-   14-O-{[3(R*)-(Isopropoxypropionyl-2(R)-amino)-cyclopent-1(R*)-yl-sulfanyl]-acetyl}-mutilin,-   14-O-{[3(S*)-(Isopropoxypropionyl-2(R)-amino)-cyclopent-1(R*)-yl-sulfanyl]-acetyl}-mutilin,    and-   14-O-{[3(S*)-(Isopropoxypropionyl-2(S)-amino)-cyclopent-1(R*)-yl-sulfanyl]-acetyl}-mutilin;-   14-O-{[(3-Methylcarbamoylmethylamino-cyclopent-1-yl)-sulfanyl]-acetyl}-mutilin,    such as-   14-O-{[(3(R/S)-Methylcarbamoylmethylamino-cyclopent-1(R/S)-yl)-sulfanyl]-acetyl}-mutilin,-   14O-[(((3-(1-Cyclohexylethyl)-amino)-cyclohexan-1-yl)-sulfanyl)-acetyl]-mutilin,    such as-   14-O-[(((3-((1(R)-Cyclohexylethyl)-(S*)-amino)-cyclohexan-1(R*)-yl)-sulfanyl)-acetyl]-mutilin,    and-   14-O-[(((3-((1(R)-Cyclohexylethyl)-(S*)-amino)-cyclohexan-1(S*)-yl)-sulfanyl)-acetyl]-mutilin,-   14-O-[(((3-(Phenylethyl)-amino)-cyclopentan-1-yl)-sulfanyl)-acetyl]-mutilin,    such as-   14-O-[(((3-((S)-Phenylethyl)-(R*)-amino)-cyclopentan-1(S*)-yl)-sulfanyl)-acetyl]-mutilin,-   14-O-[(((3-((S)-Phenylethyl)-(S*)-amino)-cyclopentan-1(S*)-yl)-sulfanyl)-acetyl]-mutilin,-   14-O-[(((3-((R)-Phenylethyl)-(R*)-amino)-cyclopentan-1(S*)-yl)-sulfanyl)-acetyl]-mutilin,    and-   14-O-[(((3-((R)-Phenylethyl)-(S*)-amino)-cyclopentan-1(S*)-yl)-sulfanyl)-acetyl]-mutilin,-   14-O-[(((3-(Phenylethyl)-amino)-cyclohexan-1-yl)-sulfanyl)-acetyl]-mutilin,    such as-   14-O-[(((3(R*)-((S)-Phenylethyl)-amino)-cyclohexan-1(R*)-yl)-sulfanyl)-acetyl]-mutilin,-   14-O-[(((3(S*)-((S)-Phenylethyl)-amino)-cyclohexan-1(R*)-yl)-sulfanyl)-acetyl]-mutilin,-   14-O-[(((3(S*)-((R)-Phenylethyl)-amino)-cyclohexan-1(R*)-yl)-sulfanyl)-acetyl]-mutilin,-   14-O-[(((3(R*)-((R)-Phenylethyl)-amino)-cyclohexan-1(R*)-yl)-sulfanyl)-acetyl]-mutilin,-   14-O-[(((3(R*)-((R)-Phenylethyl)-amino)-cyclohexan-1(S*)-yl)-sulfanyl)-acetyl]-mutilin,    and-   14-O-[(((3(S*)-((R)-Phenylethyl)-amino)-cyclohexan-1(S*)-yl)-sulfanyl-acetyl]-mutilin;-   14-O-{[3-(1H-Benzoimidazol-2-ylmethylamino)-cyclopent-1-ylsulfanyl]-acetyl}-mutilin,    such as-   14-O-{[3(R/S)-(1H-Benzoimidazol-2-ylmethylamino)-cyclopent-1(R/S)-ylsulfanyl]-acetyl}-mutilin,-   14-O-{[(3-Dimethylamino-cyclopent-1-yl)-sulfanyl]-acetyl}-mutilin,    such as-   14-O-{[(3(S*)-Dimethylamino-cyclopent-1(R*)-yl)-sulfanyl]-acetyl}-mutilin,    and-   14-O-{[(3(S*)-Dimethylamino-cyclopent-1(S*)-yl)-sulfanyl]-acetyl}-mutilin;-   14-O-{[(3-Diethylamino-cyclopent-1)-yl)-sulfanyl]-acetyl}-mutilin,    such as-   14-O-{[(3(S*)-Diethylamino-cyclopent-1(S*)-yl)-sulfanyl]-acetyl}-mutilin,    and-   14-O-{[(3(S*)-Diethylamino-cyclopent-1(R*)-yl)-sulfanyl]-acetyl}-mutilin;-   14-O-[((3-Diethylamino-cycloheptan-1-yl)-sulfanyl)-acetyl]-mutilin,    such as-   14-O-[((3(R/S)-Diethylamino-cycloheptan-1(R/S)-yl)-sulfanyl)-acetyl]-mutilin;-   14-O-{[(3-Cyclopropylamino-cyclopent-1-yl)-sulfanyl]-acetyl}-mutilin,    such as-   14-O-{[(3(R/S)-Cyclopropylamino-cyclopent-1(R/S)-yl)-sulfanyl]-acetyl}-mutilin,-   14-O-{[(3-Cyclopropylamino-cyclohexan-1-yl)-sulfanyl]-acetyl}-mutilin,    such as-   14-O-{[(3    (S)-Cyclopropylamino-cyclohexan-1(R)-yl)-sulfanyl]-acetyl}-mutilin,    and-   14-O-{[(3(R)-Cyclopropylamino-cyclohexan-1(R)-yl)-sulfanyl]-acetyl}-mutilin;-   14-O-[((3-(Morpholin-4-yl)-cyclohexan-1-yl)-sulfanyl)-acetyl]-mutilin,    such as-   14-O-[((3(R*)-(Morpholin-4-yl)-cyclohexan-1(S*)-yl)-sulfanyl)-acetyl]-mutilin,    and-   14-O-[((3(R*)-(Morpholin-4-yl)-cyclohexan-1(R*)-yl)-sulfanyl)-acetyl]-mutilin;-   14-O-{[(3-(1H-Imidazol-2-ylamino)-cyclopent-1-yl)-sulfanyl]-acetyl}-mutilin,    such as-   14-O-{[(3(R/S)-(1H-Imidazol-2-ylamino)-cyclopent-1(R/S)-yl)-sulfanyl]-acetyl}-mutilin;    and-   14-O-{[(3-(1H-Benzoimidazol-2-ylamino)-cyclopent-1-yl)-sulfanyl]-acetyl}-mutilin,    such as-   14-O-{[(3(R/S)-(1H-Benzoimidazol-2-ylamino)-cyclopent-1(R/S)-yl)-sulfanyl]-acetyl}-mutilin;    e.g. in the form of a salt, such as a hydrochloride.

A compound provided by the present invention is herein also designatedas “compound(s) of (according to) the present invention”. A compound ofthe present invention includes mutilin-14-yl acetic acid esters asdefined above, including a compound of formula I, I_(p) or I_(pp). Acompound of the present invention includes a compound in any form, e.g.in free form, in the form of a salt, in the form of a solvate and in theform of a salt and a solvate.

In another aspect the present invention provides a compound of thepresent invention in the form of a salt and/or solvate.

Such salts include preferably pharmaceutically acceptable salts,although pharmaceutically unacceptable salts are included, e.g. forpreparation/isolation/purification purposes.

A salt of a compound of the present invention includes a base salt or anacid addition salt. Pharmaceutically acceptable base salts includeammonium salts such as a trimethylammonium salt, alkali metal salts suchas those of sodium and potassium, alkaline earth metal salts such asthose of calcium and magnesium and salts with organic bases, includingsalts of primary, secondary and tertiary amines, such as isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine andN-methyl-D-glucamine. Acid addition salts include salts of a compound ofthe present invention with an acid, e.g. hydrogen fumaric acid, fumaricacid, tartaric acid, ethane-1,2-disulphonic acid, maleic acid,naphthalin-1,5-sulphonic acid, hydrochloric acid, deuterochloric acid,preferably hydrochloric acid.

A compound of the present invention in free form may be converted into acorresponding compound in the form of a salt; and vice versa. A compoundof the present invention in free form or in the form of a salt and inthe form of a solvate may be converted into a corresponding compound infree form or in the form of a salt in non-solvated form; and vice versa.

A compound of the present invention may exist in the form of isomers andmixtures thereof; e.g. optical isomers, diastereoisomers, cis/transconformers. A compound of the present invention may e.g. containasymmetric carbon atoms and may thus exist in the form of enantiomers ordiastereoisomers and mixtures thereof, e.g. racemates. Substituents atany asymmetric carbon atom may be present in the (R)-, (S)- or(R,S)-configuration, preferably in the (R)- or (S)-configuration.

For example, in a compound of formula I_(pp) the carbon atom of thecycloalkyl ring which is attached to the side sulphur atom, and thecarbon atom of the cycloalkyl ring to which the N(RR₁) group isattached, both are asymmetric carbon atoms. Substituents attached tosuch asymmetric carbon atom may thus exist in (R) and (S) configuration,including mixtures thereof. For example, if R₂ in a compound of formulaI_(pp) is other than hydrogen, the carbon atom to which R₂ is attachedis an asymmetric carbon atom and R₂ thus may exist in (R) and (S)configuration, including mixtures thereof.

For example, if in a compound of formula I R₁ is substituted alkyl andthat substituent is attached to a carbon atom of the side chain of suchalkyl, the carbon atom to which such substituent is attached is anasymmetric carbon atom and such substituent may be in the (R)- and(S)-configuration, including mixtures thereof. The configuration ofsubstituents attached to asymmetric carbon atoms of the mutilin-ring ispreferably the same as in natural pleuromutilin.

Isomeric mixtures may be separated as appropriate, e.g. according, e.g.analogously, to a method as conventional, to obtain pure isomers. Thepresent invention includes a compound of the present invention in anyisomeric form and in any isomeric mixture. The present invention alsoincludes tautomers of a compound of the present invention, wheretautomers can exist.

Any compound described herein, e.g. a compound of the present inventionand intermediates in their production may be prepared as appropriate,e.g. according, e.g. analogously, to a method as conventional, e.g. oras specified herein.

In another aspect the present invention provides a process for thepreparation of 14-O-[((Mono- or dialkylamino)-cycloalkylsulfanyl- or-cycloalkyl-oxy)-acetyl, -thioacetyl or -imino-oxy]-mutilins;14-O-[((Cycloalkyl- or heterocyclylamino)-cycloalkylsulfanyl- or-cycloalkyl-oxy)-acetyl, -thioacetyl or -imino-oxy]-mutilins;14-O-[((Heterocyc-N-yl-cycloalkyl)-sulfanyl- or -oxy)-acetyl,-thioacetyl or -imino-oxy]-mutilins; 14-O[(((Mono- ordialkylamino)-cycloalkyl)-alkylsulfanyl- or alkyl-oxy)-acetyl,-thioacetyl or -imino-oxy]-mutilins; 14-O-[(((Cycloalkyl- orheterocyclylamino)-cycloalkyl)-alkylsulfanyl- or -alkyl-oxy)-acetyl,-thioacetyl or -imino-oxy]-mutilins; or14-O-[((Heterocyc-N-yl-cycloalkyl)-alkylsulfanyl- or -alkyl-oxy)-acetyl,-thioacetyl or -imino-oxy]-mutilins, respectively, comprising

-   a. reacting a 14-O-[(Cycloalkanone-sulfanyl- or    cycloalkanone-oxy)-acetyl, -thioacetyl or -imino-oxy]-mutilin or a    14-O-[(Cycloalkanone-alkylsulfanyl- or    Cycloalkanone-alkyl-oxy)-acetyl, -thioacetyl or -imino-oxy]-mutilin,    respectively, with an amine, e.g. including a heterocyclic amine    comprising at least one nitrogen atom as a heteroatom, in the    presence of titanium isopropoxide,-   b. treating the mixture obtained with sodium cyano boronhydride in    dry organic solvent, e.g. absolute ethanol, and adding water, and-   c. isolating 14-O-[((Mono- or dialkylamino)-cycloalkylsulfanyl- or    -cycloalkyl-oxy)-acetyl, -thioacetyl or -imino-oxy]-mutilins;    14-O-[((Cycloalkyl- or heterocyclylamino)-cycloalkylsulfanyl- or    -cycloalkyl-oxy)-acetyl, -thioacetyl or -imino-oxy]-mutilins;    14-O-[((Heterocyc-N-yl-cycloalkyl)-sulfanyl- or -oxy)-acetyl,    -thioacetyl or -imino-oxy]-mutilins; 14-O-[(((Mono- or    dialkylamino)-cycloalkyl)-alkylsulfanyl- or -alkyl-oxy)-acetyl,    -thioacetyl or -imino-oxy]-mutilins; 14-O-[(((Cycloalkyl- or    heterocyclylamino)-cycloalkyl)-alkylsulfanyl- or -alkyl-oxy)-acetyl,    -thioacetyl or -imino-oxy]-mutilins; or    14-O-[((Heterocyc-N-yl-cycloalkyl)-alkylsulfanyl- or    -alkyl-oxy)-acetyl, -thioacetyl or -imino-oxy]-mutilins,    respectively, from the reaction mixture.

In another aspect the present invention provides a process for thepreparation of a compound of formula I, comprising the following steps

-   a. reacting a compound of formula II

-    wherein X, Y, R₂, R₃, R′₃, R₄, R₅, R₆, R₇, R₈, n and p are as    defined above, with an amine of formula —N(R)(R₁), wherein R and R₁    are as defined above, in the presence of titanium isopropoxide,-   b. treating the mixture obtained in step a with sodium cyano    boronhydride in dry organic solvent, e.g. absolute ethanol and    adding water,-   b. and isolating a compound of formula I, wherein X, Y, R, R₁, R₂,    R₃, R′₃, R₄, R₅, R₆, R₇, R₈, n and p are as defined above, from the    reaction mixture.

A 14-O-[(Cycloalkanone-sulfanyl- or cycloalkanone-oxy)-acetyl,-thioacetyl or -imino-oxy]-mutilin, e.g. a compound of formula II may beobtained as appropriate, e.g. according, e.g. analogously to a method asconventional, e.g. reacting a cycloalkanone with 14-O-[(Mercapto- orhydroxy)-acetyl, -thioacetyl or -imino-oxy]-mutilin, in the presence ofan amine, e.g. triethylamine, and isolating a14-O-[(Cycloalkanone-sulfanyl- or cycloalkanone-oxy)-acetyl, -thioacetylor -imino-oxy]-mutilin, such as a compound of formula H, from thereaction mixture obtained.

A compound according to the present invention or an intermediate in thepreparation of a compound of the present invention may e.g. also beobtained according, e.g. analogously, to a method as disclosed inWO0204414.

A compound obtained by a process provided by the present invention maybe converted into a corresponding salt, according, e.g. analogously, toa method as conventional, e.g. by treatment with an acid, or, a basesuch as metal base or organic base, respectively, to obtain an acidaddition salt, or, a base addition salt, respectively and vice versa. Acompound obtained by a process provided by the present invention in theform of a salt may be converted into the corresponding compound in theform of a free base, according, e.g. analogously, to a method asconventional, e.g. by treatment with an acid if a base addition salt isobtained and by treating with a base if an acid addition salt isobtained.

The compounds of the present invention exhibit pharmacological activityand are therefore useful as pharmaceuticals.

For example, the compounds of the present invention show antimicrobial,e.g. antibacterial, activity against gram positive bacteria, such ascoagulase positive Staphylococci, e.g. Staphylococcus aureus, coagulasenegative Staphylococci, e.g. Staphylococcus epidermidis, Staphylococcushaemolyticus, and Streptococci, e.g. Streptococcus pyogenes,Streptococcus pneumoniae, Enterococci, e.g. Enterococcus faecium, andListeria monocytogenes, and against gram negative bacteria such asMoraxella, e.g. Moraxella catarrhalis, and Haemophilus, e.g. Haemophilusinfluenzae, and Legionella, e.g. Legionella pneumophila, Neisseriaceae,e.g. Neisseria gonorrhoeae, as well as against Mycoplasms, Chlamydia andobligatory anaerobes, e.g. Bacteroides fragilis, Clostridium difficile,Fusobacterium spp., and Propionibacterium spp.

The in vitro activity against aerobic bacteria was determined by AgarDilution Test or Microdilution Test according to the Clinical andLaboratory Standards Institute (CLSI, former NCCLS) Document M7-A7 Vol.26, No. 2: “Methods for dilution Antimicrobial Susceptibility Tests forBacteria that Grow Aerobically—Approved Standard; Seventh Edition(2006)”; and the test against anaerobic bacteria was performed accordingto the Clinical and Laboratory Standards Institute (CLSI, former NCCLS),Document, M11-A6, Vol. 24, No. 2: “Methods for AntimicrobialSusceptibility Testing of Anaerobic Bacteria—Approved Standard; SixthEdition (2004)” and the in vivo activity was tested by the septicaemiamouse model against Staphylococcus aureus.

Compounds of the present invention are therefore suitable for thetreatment and prevention of diseases which are mediated by microbes,e.g. by bacteria. Diseases which may also be treated include e.g.diseases mediated by Helicobacter, such as Helicobacter pylori, anddiseases mediated by Mycobacterium tuberculosis. Diseases which may alsobe treated include in general inflammatory diseases, where microbes aremediating said inflammation, e.g. including acne.

In another aspect the present invention provides a compound of thepresent invention for use as a pharmaceutical, preferably as anantimicrobial, such as an antibiotic, e.g., and an anti-anaerobic.

In another aspect the present invention provides a compound of thepresent invention for use in acne treatment.

In a further aspect the present invention provides a compound of thepresent invention for use in the preparation of a medicament for thetreatment of diseases, mediated by microbes, such as bacterials, forexample

diseases mediated by bacteria, e.g. selected from Staphylococci,Streptococci, Enterococci;

diseases mediated by bacteria, e.g. selected from Moraxella,Haemophilus, Legionella, Neisseriaceae;

diseases mediated by Helicobacter

diseases mediated by Mycobacterium tuberculosis,

e.g. diseases mediated by Mycoplasms, Chlamydia and obligatoryanaerobes,

and for the treatment of acne.

In a further aspect the present invention provides a method of treatmentof diseases mediated by microbes which comprises administering to asubject in need of such treatment an effective amount of a compound ofthe present invention, e.g. in the form of a pharmaceutical composition.

In a further aspect the present invention provides a method of treatmentof acne which comprises administering to a subject in need of suchtreatment an effective amount of a compound of the present invention,e.g. in the form of a pharmaceutical composition.

Treatment includes treatment and prophylaxis.

For antimicrobial and acne treatment, the appropriate dosage will, ofcourse, vary depending upon, for example, the chemical nature and thepharmakokinetic data of a compound of the present invention employed,the individual host, the mode of administration and the nature andseverity of the conditions being treated. However, in general, forsatisfactory results in larger mammals, for example humans, an indicateddaily dosage is in the range from about 0.5 mg to 3 g of a compound ofthe present invention, conveniently administered, for example, individed doses up to four times a day.

A compound of the present invention may be administered by anyconventional route, for example enterally, e.g. including nasal, buccal,rectal, oral administration; parenterally, e.g. including intravenous,intramuscular, subcutaneous administration; or topically, e.g. includingepicutaneous, intranasal, intratracheal administration, e.g. in form ofcoated or uncoated tablets, capsules, injectable solutions orsuspensions, e.g. in the form of ampoules, vials, in the form of creams,gels, pastes, inhaler powder, foams, tinctures, lip sticks, drops,sprays, or in the form of suppositories, e.g. in analogous manner tomacrolides, such as erythromycins, e.g. clarithromycin or azithromycin.

A compound of the present invention may be administered in the form of apharmaceutically acceptable salt, e.g. an acid addition salt or metalsalt; or in free form; optionally in the form of a solvate. A compoundof the present invention in the form of a salt exhibits the same orderof activity as the compound in free form; optionally in the form of asolvate.

A compound of the present invention may be used for pharmaceuticaltreatment according to the present invention alone or in combinationwith one or more other pharmaceutically active agents. Such otherpharmaceutically active agents include e.g. other antibiotics andantiinflammatory agents, and, if a compound of the present invention isused in the treatment of acne, other pharmaceutically agents includefurthermore agents which are active against acne.

Combinations include fixed combinations, in which two or morepharmaceutically active agents are in the same formulation; kits, inwhich two or more pharmaceutically active agents in separateformulations are sold in the same package, e.g. with instruction forco-administration; and free combinations in which the pharmaceuticallyactive agents are packaged separately, but instruction for simultaneousor sequential administration are given.

In another aspect the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention in free formor in the form of a pharmaceutically acceptable salt and/or in the formof a solvate in association with at least one pharmaceutical excipient,e.g. carrier or diluent, e.g. including fillers, binders,disintegrators, flow conditioners, lubricants, sugars and sweeteners,fragrances, preservatives, stabilizers, wetting agents and/oremulsifiers, solubilizers, salts for regulating osmotic pressure and/orbuffers.

In another aspect the present invention provides a pharmaceuticalcomposition according to the present invention, further comprisinganother pharmaceutically active agent.

Such pharmaceutical compositions may be manufactured according, e.g.analogously, to a method as conventional, e.g. by mixing, granulating,coating, dissolving or lyophilizing processes. Unit dosage form maycontain, for example, from about 0.5 mg to about 1000 mg, such as 1 mgto about 100 mg.

The compounds of the present invention are additionally suitable asveterinary agents, e.g. veterinary active compounds, e.g. in theprophylaxis and in the treatment of microbial, e.g. bacterial diseases,in animals, such as fowl, pigs and calves, e.g., and for diluting fluidsfor artificial insemination and for egg-dipping techniques.

In another aspect the present invention provides a compound of thepresent invention for use as a veterinary agent.

In a further aspect the present invention provides a compound of thepresent invention for the preparation of a veterinary composition whichis useful as a veterinary agent.

In another aspect the present invention provides a veterinary method forthe prophylaxis and in the treatment of microbial, e.g. bacterialdiseases which comprises administering to a subject in need of suchtreatment an effective amount of a compound of the present invention,e.g. in the form of a veterinary composition.

For use of the active compounds of the present invention as a veterinaryagent, the dosage will of course vary depending upon the size and age ofthe animal and the effect desired; for example for prophylactictreatment relatively low doses would be administered over a longer timeperiod, e.g. 1 to 3 weeks. Preferred doses in drinking water are from0.0125 to 0.05 weight by volume, particularly 0.0125 to 0.025; and infoodstuffs from 20 to 400 g/metric ton, preferably 20 to 200 g/metricton. It is preferred to administer the active compounds of the presentinvention as a veterinary agent to hens in drinking water, to pigs infoodstuff and to calves orally or parenterally, e.g. in the form of oralor parenteral preparations.

In the following examples all temperatures are in degrees Celsius (° C.)and are uncorrected.

EXAMPLE 114-O-[(3(R*)-Diethylamino-cyclohexan-1(S*)-yl)-sulfanylacetyl]-mutilinin the form of a hydrochloride and14-O-[(3-(R*)-Diethylamino-cyclohexan-1-(R*)-yl)-sulfanylacetyl]-mutilinin the form of a hydrochloride A. 14-O-Mercaptoacetyl-mutilin

A mixture of 15.2 g of thiourea and 106.4 g ofpleuromutilin-22-O-tosylate in 250 ml of acetone is heated under refluxfor 1.5 hours, from the mixture obtained solvent is evaporated and tothe evaporation residue 100 ml of hexane are added. A precipitate formsand is isolated. To a solution of 12.2 g of the isolated precipitate ina mixture of 20 ml ethanol and 35 ml H₂O (heated to 90°), a solution of4.7 g of Na₂S₂O₅ in 25 ml of H₂O and 100 ml of CCl₄ are added. Themixture obtained is heated under reflux for 2 hours, The organic phaseis separated, dried, and solvent is evaporated to dryness.14-O-Mercaptoacetyl-mutilin is obtained which may be used in furtherreaction steps without further purification. ¹H-NMR (CDCl₃): ABX-system(ν_(A)=3.15, ν_(B)=3.22, ν_(x)=1.92, 2H, H₂₂, J=15.8 Hz, J=8.2 Hz). MSm/e: 417 (M⁺+Na).

B. 14-O-[(Cyclohexanone-3(R/S)-yl)-sulfanylacetyl]-mutilin

A mixture of 1.92 g of cyclohexenone, 7.88 g of14-O-mercaptoacetylmutilin and 0.5 ml of triethylamine is stirred inpyridine at 25° for 15 hours. To the mixture obtained ethyl acetate isadded and the mixture obtained is extracted with 1N HCl and repeatedlywashed with brine. From the organic phase solvent is evaporated (todryness). 14-O-[(Cyclohexanone-3(R/S)-yl)-sulfanylacetyl]-mutilin isobtained which may be used in further reaction steps without furtherpurification. ¹H-NMR (CDCl₃)): 3.22 (m, 1H, SCH), AB-system:(ν_(A)=3.29, ν_(B)=3.37, 2H, H₂₂, J=14.8 Hz). MS m/e: 513 (M⁺+Na).

B1. 14-O-[(Cycloheptanone-3(R/S)-yl)-sulfanylacetyl]-mutilin is preparedanalogously to the method of Example 1, step B., but using appropriatestarting materials. ¹H-NMR (d₆-DMSO): AB-system: (ν_(A)=3.32,ν_(B)=3.22, 2H, H₂₂, J=14.8 Hz), 3.15 (m, 1H, SCH), AB-system:(ν_(A)=2.75, ν_(B)=2.62, 2H, COCH₂CHS, J=14 Hz).14-O-[(Cycloheptanone-3(R/S)-yl)-sulfanylacetyl]-mutilin is not used inExample 1 but as a starting material in other examples.

B2. 14-O-[(Cyclopentanone-3(R/S)-yl)-sulfanylacetyl]-mutilin

is prepared analogously to the method of Example 1, step B., but usingappropriate starting materials. ¹H-NMR (CDCl₃)): 3.6 (m, 1H, SCH),AB-system: (ν_(A)=3.25, ν_(B)=3.17, 2H, H₂₂, J=14.8 Hz), AB-system:(ν_(A)=2.55, ν_(B)=2.2, 2xm, 2H, CHCH₂CO).14-O-[(Cyclopentanone-3(R/S)-yl)-sulfanylacetyl]-mutilin is not used inExample 1 but as a starting material in other examples.

C.14-O-[(3(R*)-Diethylamino-cyclohexan-1(S*)-yl)-sulfanylacetyl]-mutilinin the form of a hydrochloride and14-O-[(3-(R*)-Diethylamino-cyclohexan-1-(R*)-yl)-sulfanylacetyl]-mutilinin the form of a hydrochloride

A mixture of 5.39 g of14-O-[(Cyclohexanone-3(R/S)-yl)-sulfanylacetyl]-mutilin, 803 mg ofdiethyl amine and 3.9 g of titanium(IV) isopropoxide is stirred at 25°for 1 to 8 hours, then 456 mg of sodium cyano boronhydride and 10 mlabsolute ethanol are added. The reaction mixture is kept at 25° for 3hours. 10 ml of water are added and the mixture obtained is extractedwith acetic acid ethyl ester. The organic phase is dried and solvent isevaporated to dryness. The evaporation residue is subjected tochromatography on silica gel (EE/MeOH 1:1) to yield 1.58 g of14-O-[(3(R*)-Diethylamino-cyclohexan-1(S*)-yl)-sulfanylacetyl]-mutilinand 2.81 g of14-O-[(3-(R*)-Diethylamino-cyclohexan-1-(R*)-yl)-sulfanylacetyl]-mutilin.Hydrochlorides of14-O-[(3(R*)-Diethylamino-cyclohexan-1(S*)-yl)-sulfanylacetyl]-mutilinand14-O-[(3-(R*)-Diethylamino-cyclohexan-1-(R*)-yl)-sulfanylacetyl]-mutilinare obtained by treating the free amines with 0.1 N HCl in ether.

Analogously to a method as set out in Example 1, but using appropriatestarting materials, a compound of formula EX

wherein CYC and R_(EX) are as defined in TABLE 1 below are obtained.

TABLE 1 EX R_(EX) CYC DATA  1a

C614-O-[(3(R*)-Diethylamino-cyclohexan-1(S*)-yl)-sulfanylacetyl]-mutilin:10.05 (b, 1H, NH⁺),6.15 (dd, 1H, H₁₉, J = 17.6 Hz, J = 11.2 Hz), 5.6(d,1H, H₁₄, J = 8.2 Hz), 5.05 (m, 2H, H₂₀), AB-System: v_(A) = 3.44, v_(B)= 3.33 (2H, SCH₂,J = 14.9 Hz), 3.05, 3.2 (2xb, 5H, NCH₂, NCH), 2.8(b,1H, SCH), 2.4 (b, 1H, H₄), 1.34 (s, 3H,(CH₃)₁₅), 1.25 (t, 6H, NCH₂CH₃, J= 8.2 Hz), 1.05(s, 1H, (CH₃)₁₈), 0.81 (d, 3H, (CH₃)₁₇, J = 6.9 Hz),0.63(m, 3H, (CH₃)₁₆). MS m/e: 548 (MH⁺).  1b14-O-[(3(R*)-Diethylamino-cyclohexan-1(R*)- yl)-sulfanylacetyl]-mutilin:9.5 (b, 1H, NH⁺), 3.35 (m, 2H, H₂₂,) 3.05, 3.18 (2xb, 5H, NCH₂, NCH),1.25 (t, 6H, NCH₂CH₃, J = 8.2 Hz), MS m/e: 548 (MH⁺)  2

C514-O-{[(3(R/S)-Methylamino-cyclopent-1(R/S)-yl)-sulfanyl]-acetyl}-mutilin:8.8 (b, 2H, NH₂ ⁺),3.55 (m, 1H, NCH)), 3.15 (m, 1H, SCH), MS m/e:492(M⁺)  3

C514-O-{[(3(R/S)-Ethylamino-cyclopent-1(R/S)-yl)-sulfanyl]-acetyl}-mutilin:8.8 (b, 2H, NH₂ ⁺),3.55, 3.35 (2xm, 1H, NCH)), 3.15 (m, 1H, SCH),2.88(q, 2H, NCH₂CH₃, J = 7.2 Hz), 1.18 (t, 3H, CH₂CH₃,J = 7.2 Hz), MSm/e: 506 (MH⁺)  4

14-O-{[(3(R/S)-Ethylamino-1-methyl-cyclopent-1(R/S)-yl)-sulfanyl]-acetyl}-mutilin:8.8(b, 2H, (NH₂)⁺), 3.6 (m, 1H, NCH), 2.9 (m, 2H,NCH₂), 3.35 (m, 2H,H₂₂), 1.3 (s, 3H, SCCH₃), MSm/e: 520 (MH⁺)  5

14-O-{[(3(R/S)-Ethylamino-2-methyl-cyclopent-1(R/S)-yl)-sulfanyl]-acetyl}-mutilin:8.3-8.9(b, 2H, (NH₂)⁺), 2.7, 2.85, 3.1 (3xm, 4H, SCH, NCH,NCH₂), 3.35(m, 2H, H₂₂), 1.2 (m, 6H, NCH, CH₃,CCH₃), MS m/e: 520 (MH⁺)  6a

C6 14-O-{[3-Ethylamino-cyclohexylsulfanyl]-acetyl}-mutilin: 8.6 (b, 2H,NH₂ ⁺), 3.3 (m, 4H,NCH₂CH₃, H₂₂), 2.95 (m, 2H, NCH, SCH), 1.18 (t,3H,CH₃CH₂), MS m/e: 520 (MH⁺)  6b 14-O-{[3(S)-Ethylamino-cyclohex-1(R)-ylsulfanyl]-acetyl}-mutilin + 1S3R-Diastereomer: 8.65 (b, 2H, NH₂ ⁺),3.35 (m, 2H, H₂₂), 2.95, 2.75 (2xm, 3H, NCH₂CH₃, NCH, SCH), 1.18 (t, 3H,NCH₂CH₃), MS m/e: 520 (MH⁺)  6c 14-O-{[3(R)-Ethylamino-cyclohex-1(R)-ylsulfanyl]-acetyl}-mutilin + 1S3S-Diastereomer: 8.6 (b, 2H, NH₂ ⁺),3.40-3.15 (m, 4H, H₂₂, NCH, SCH), 2.93 (q, 2H, NCH₂CH₃), 1.17 (t, 3H,NCH₂CH₃), MS m/e: 520 (MH⁺)  7a

C514-O-{[3-(R/S)-((S)-sec-Butylamino)-cyclopent-1(R/S)-ylsulfanyl]-acetyl}-mutilin:8.75,8.6 (2xb, 2H, NH₂ ⁺), 3.15, 3.6 (2xb, 2H, NCH,NCHCH₃), 3.05 (b, 1H,SCH), 1.18 (d, 3H, CH₃CH,4.4 Hz), 0.88 (t, 3H, CH₃CH₂), MS m/e: 534(MH⁺)  7b 14-O-{[3-(R/S)-((R)-sec-Butylamino)-cyclopent-1(R/S)-ylsulfanyl]-acetyl}-mutilin: 8.85, 8.65 (2xb, 2H, NH₂ ⁺), 3.15,3.6, 3.7 (3xb, 2H, NCH, NCHCH₃), 3.3 (m, 2H, H₂₂), 3.02 (b, 1H, SCH),1.18 (m, 3H, CH₃CH) 0.88 (t, 3H, CH₃CH₂), MS m/e: 534 (MH⁺)  8a

C614-O-[(3-(S*)-(sec-(R)-Butylamino)-cyclohexan-1-(R*)-yl)-sulfanyl)-acetyl]-mutilin:3.3(b, 2H, NH₂ ⁺), 3.3 (m, 2H, H₂₂) 3.1, 3.2 (2xb, 2H,2 x NCH), 2.75 (b,1H, SCH), 1.18 (d, 3H, CH₃CH,4.4 Hz), 0.9 (t, 3H, CH₃CH₂, J = 8.4 Hz) 8b 14-O-[(3-(S*)-(sec-(R)-Butylamino)-cyclohexan-1-(S*)-yl)-sulfanyl-acetyl]-mutilin: 8.55 (b, 2H, NH₂ ⁺), 3.4 (m, 2H,H₂₂) 3.15 (b, 1H, SCH), 1.18 (d, 3H, CH₃CH, 4.4 Hz), 0.9 (t, 3H, CH₃CH₂,J = 8.4 Hz)  8c 14-O-[(3-(S*)-(sec-(S)-Butylamino)-cyclohexan-1-(S*)-yl)-sulfanyl-acetyl]-mutilin: 8.45, (b, 2H, NH₂ ⁺), 3.4 (m, 2H,H₂₂) 3.05 (b, 1H, SCH), 3.2 (b, 1H, NCH), 1.18 (d, 3H, CH₃CH, 4.4 Hz),0.9 (t, 3H, CH₃CH₂, J = 8.4 Hz)  8d14-O-[(3-(S*)-(sec-(S)-Butylamino)-cyclohexan-1-(R*)-yl)-sulfanyl-acetyl]-mutilin: 8.45, 8.55 (2xb, 2H, NH₂ ⁺),AB-system (v_(A) = 3.35, v_(B) = 3.42, H₂₂, J = 14.5 Hz), 3.15 (b, 1H,SCH), 1.18 (d, 3H, CH₃CH, 4.4 Hz), 0.9 (t, 3H, CH₃CH₂, J = 8.4 Hz)  9

C714-O-[1-((R/S)-(sec-(R)-Butylamino)-cycloheptane-3(R/S)-yl)-sulfanyl-acetyl}-mutilin:8.65,8.55 (2xb, 2H, NH₂ ⁺), 3.4-3.45 (m, 3H, H₁₁, H₂₂),2.9 (b, 1H, SCH),3.1-3.3 (m, 3H, NCH, NCHCH₃),1.18 (d, 3H, CH₃CH, 4.4 Hz), 0.9 (m, 3H,CH₃CH₂) 10

C514-O-{[3(R/S)-(2,2,2-Trifluoro-ethylamino)-cyclopent-1(R/S)-ylsulfanyl]-acetyl}-mutilin:9.9(b, 2H, (NH₂)⁺), 3.55, 3.7, 4.0 (3xb,3H, NCH₂, NCH), 3.3 (m, 2H, H₂₂),3.1 (m, 1H, SCH) 11

C614-O-{[3(R/S)-(2,2,2-Trifluoro-ethylamino)-cyclohexan-1(R/S)-ylsulfanyl]-acetyl}-mutilin:3.1-3.3(m, 5H, H₂₂, NCH₂CF₃), 2.35, 2.65, 2.78(3xm, 2H, NCH, SCH), MS m/e: 574(MH⁺),596 (MNa⁺) 12

C614-O-{[3(R/S)-(2,2-Difluoro-ethylamino)-cyclohexan-1(R/S)-ylsulfanyl]-acetyl}-mutilin:5.7-6.05(m, 1H, NCH₂CHF₂), 3.1-3.3 (m, 2H,H₂₂), 2.85 (m, 2H, NCH₂CHF₂), 2.35,2.65, 2.74(3xm, 2H, NCH, SCH), MS m/e: 556 (MH⁺),578 (MNa⁺) 13

C514-O-{[3(R/S)-(2-Hydroxy-ethylamino)-cyclopent-1(R/S)-yl)-sulfanyl]-acetyl}-mutilin:8.2-8.7(b, 2H, (NH₂)⁺), 5.15 (b, 1H, CH₂OH),3.6 (m, 2H, CH₂OH), 3.3 (m, 2H,H₂₂), 3.1(m, 1H, SCH), 2.9 (m, 2H, NCH₂CH₂OH), MSm/e: 522 (MH⁺) 14a

C5 14-O-{[3-(R/S)-(2-(S)-Hydroxy-propylamino)-cyclopent-1(R/S)-ylsulfanyl]-acetyl}-mutilin:8.5-8.9 (2xb, 2H, (NH₂)⁺), 5.3 (d, 1H, OH, J = 4.4 Hz),3.3 (m, 2H, H₂₂),3.9 (m, 1H, CHOH), AB-system (v_(A) =2.9, v_(B) = 2.7, 2H, NCH₂CH), 3.1(m, 1H, SCH),2.4 (m, 1H, NCH), 1.1 (d, 3H, CHCH₃) 14b14-O-{[3-(R/S)-(2-(R)-Hydroxy-propylamino)-cyclopent-1(R/S)-ylsulfanyl]-acetyl}-mutilin: 8.6- 8.75 (2xb, 2H,(NH₂)⁺), 3.3 (m, 2H, H₂₂), 3.9 (m, 1H, CHOH), AB-system (v_(A) = 2.9,v_(B) = 2.7, 2H, NCH₂CH), 3.1 (m, 1H, SCH), 2.4 (m, 1H, NCH), 1.1 (d,3H, CHCH₃) 15

C514-O-[((3(R/S)-(1(S)-Isopropyl-2-hydroxy-ethylamino)-cyclopent-1(R/S)-yl)-sulfanyl)-acetyl]-mutilin:8.35, 8.75 (2xb, 2H, (NH₂)⁺), 5.3(b, 1H, OH), 3.55-3.7 (b, 2H, OCH₂),2.9, 3.0, 3.3 (3xb,2xNCH, SCH), 3.25 (m, 2H, H₂₂),1.0 (m, 6H, CH(CH₃)₂),MS m/e: 550 (MH⁺). 16

C614-O-[((3-(R/S)-(1(S)-Isopropyl-2-hydroxy-ethyl-amino)-cyclohexan-1-(R/S)-yl)-sulfanyl)-acetyl]-mutilin:8.05, 8.35 (2xb, 2H, NH₂ ⁺), 5.3 (b, 1H, OH),3.65 (b, 2H, CH₂OH),AB-system (v_(A) = 3.35, v_(B) =3.42, H₂₂, J = 14.5 Hz), 3.18 (b, 2H,NCHCH₂, NCH),2.7 (b, 1H, SCH), 1.18 (d, 3H, CH₃CH, 4.4 Hz),0.9, 1.0(2xd, 6H, (CH₃)₂CH, J = 6.7 Hz). 17

C514-O-{[3(R/S)-(2-Hydroxy-1-hydroxymethyl-1-methyl-ethylamino)-cyclopent-1(R/S)-ylsulfanyl]-acetyl}-mutilin:4.25 (b, 2H, OH),3.25 (m, 1H, NCH), 3.3 (m, 2H, H₂₂), 3.12 (s,4H,CH₂OH), 3.05 (b, 1H, SCH), 0.85 (s, 3H, CCH₃) 18

C514-O-{[3(R/S)-(2-Hydroxy-1,1-bis-hydroxymethyl-ethylamino)-cyclopent-1(R/S)-ylsulfanyl]-acetyl}-mutilin:8.2 (b, 2H, (NH₂)⁺),3.6 (s, 6H, CH₂OH), 3.3 (m, 2H, H₂₂), 3.1 (m,1H,SCH), MS m/e: 582 (MH⁺) 19

C514-O-[((3(R/S)-(Methoxycarbonylmethyl-amino)-cyclopent-1(R/S)-yl)-sulfanyl)-acetyl]-mutilin:9.38 (b, 1H, (NH₂)⁺), 3.98 (bs, 2H,COCH₂N), 3.72 (s, 3H, OCH₃), 3.25 (m,2H, H₂₂)3.12, 3.44, 3.62 (3xm, 2H, NCH, SCH), MS m/e:550 (MH⁺) 20

C514-O-[(((3(R/S)-(Ethoxycarbonylmethyl-amino)-cyclopent-1(R/S)-yl)-sulfanyl)-acetyl]-mutilin:9.35(b, 1H, (NH₂)⁺), 4.2 (q, 2H, OCH₂CH₃, J =6.8 Hz), 3.95 (s, 2H, COCH₂N),3.98b, 1H, NHCH₂),3.25 (m, 2H, H₂₂) 3.12, 3.44, 3.62 (3xm, 2H, NCH,SCH),1.25 (t, 3H, OCH₂CH₃), J = 6.8 Hz), MS m/e:564 (MH⁺) 21

C514-O-[((3(R/S)-(Isopropoxycarbonyl-methyl-amino)-cyclopent-1(R/S)-yl)-sulfanyl)-acetyl]-mutilin:9.35 (2xb, 2H, (NH₂)⁺), 3.98b, 1H, NHCH₂),3.25 (m, 2H, H₂₂, J = 14.5Hz), 3.15, 3.45, 3.6(3xm, 2H, NCH, SCH), 1.25 (d, 6H, OCH(CH₃)₂,J = 6.5Hz), MS m/e: 578 (MH⁺) 22

C514-O-{[3(S*)-(Methoxypropionyl-2(S)-amino)-cyclopent-1(R*)-yl-sulfanyl]-acetyl}-mutilin:9.3,9.55 (2xb, 2H, NH₂ ⁺), 4.1 (m, 1H, NCHCH₃), 3.55(m, 1H, NCH)), 3.75 (s,3H, OCH₃), 3.12 (m, 1H, SCH),MS m/e: 564 (M⁺). 23a

C514-O-{[3(R*)-(Isopropoxypropionyl-2(S)-amino)-cyclopent-1(R*)-yl-sulfanyl]-acetyl}-mutilin +1S*3S*Diastereomer: 9.25, 9.6(2xb, 2H, (NH₂)⁺), 5.05 (m, 3H, COOCH,H₂₀),4.05 (b, 1H, COCHN), 3.65 (m, 1H, NCH), 3.3 (m, 2H,H₂₂), 1.25 (m,6H, OCH(CH₃)₂), 1.45 (d, 3H,NCHCH₃), MS m/e: 592 (MH⁺) 23b14-O-{[3(R*)-(Isopropoxypropionyl-2(R)-amino)-cyclopent-1(R*)-yl-sulfanyl]-acetyl}- mutilin +1S*3S*Diastereomer: 9.25, 9.55 (2xb, 2H, (NH₂)⁺), 5.05 (m, 3H, COOCH,H₂₀), 4.05 (b, 1H, COCHN), 3.65 (m, 1H, NCH), 3.3 (m, 2H, H₂₂), 1.25 (m,6H, OCH(CH₃)₂), 1.45 (d, 3H, NCHCH₃), MS m/e: 592 (MH⁺) 23c14-O-{[3(S*)-(Isopropoxypropionyl-2(R)-amino)-cyclopent-1(R*)-yl-sulfanyl]-acetyl}- mutilin +1S*3R*Diastereomer: 9.3, 9.6 (2xb, 2H, (NH₂)⁺), 5.05 (m, 3H, COOCH,H₂₀), 4.0 (b, 1H, COCHN), 3.3 (m, 2H, H₂₂), 3.15 (b, 1H, SCH), 1.25 (m,6H, OCH(CH₃)₂), 1.45 (d, 3H, NCHCH₃), MS m/e: 592 (MH⁺) 23d14-O-{[3(S*)-(Isopropoxypropionyl-2(S)-amino)-cyclopent-1(R*)-yl-sulfanyl]-acetyl}-mutilin + 1S*3R*Diastereomer: 9.3,9.6 (2xb, 2H, (NH₂)⁺), 4.95 (m, 3H, COOCH, H₂₀), 4.0 (b, 1H, COCHN), 3.3(m, 2H, H₂₂), 3.15 (b, 1H, SCH), 1.25 (m, 6H, OCH(CH₃)₂), 1.45 (d, 3H,NCHCH₃), MS m/e: 592 (MH⁺) 24

C514-O-{[(3(R/S)-Methylcarbamoylmethyl-amino-cyclopent-1(R/S)-yl)-sulfanyl]-acetyl}-mutilin:9.1,8.4 (2xb, 3H, NH, (NH₂)⁺),3.6 (bs, 2H, COCH₂N), 3.1 (b, 1H,SCH), 2.62(d, 3H, NCH₃, J = 4.6 Hz), MS m/e:549 (MH⁺) 25a

C614-O-[((3-((1-(R)-Cyclohexyl-ethyl)-(S)-amino)-cyclohexan-1-(R)-yl)-sulfanyl)-acetyl]-mutilin+RS-Diastereomeres: 8.05, 8.45 (2xb, 2H, NH₂ ⁺),AB-system (v_(A) = 3.35,v_(B) = 3.42, H₂₂, J = 14.5 Hz),3.05, 3.2 (2xb, 2H, NCHCH3, NCH),2.75(b, 1H, SCH), 1.18 (d, 3H, CH₃CH, 4.4 Hz) 25b14-O-[((3-((1(R)-Cyclohexyl-ethyl)-(S)-amino)-cyclohexan-1-(S)-yl)-sulfanyl)-acetyl]-mutilin + SS-Diastereomeres:8.05, 8.45 (2xb, 2H, NH₂ ⁺), AB-system (v_(A) = 3.35, v_(B) = 3.42, H₂₂,J = 14.5 Hz), 3.18 (b, 1H, SCH), 1.18 (d, 3H, CH₃CH, 4.4 Hz 25c14-O-[((3-((1-(R)-Cyclohexyl-ethyl)-(S*)-amino)-cyclohexan-1-(R*)-yl)-sulfanyl)-acetyl]-mutilin: 8.15, 8.55 (2xb, 2H,NH₂ ⁺), AB-system (v_(A) = 3.35, v_(B) = 3.42, H₂₂, J = 14.5 Hz), 3.18,3.05 (b, 2H, NCHCH₂, NCH), 2.75 (b, 1H, SCH), 1.12 (d, 3H, CH₃CH, 4.4Hz) 25d 14-O-[((3-((1(R)-Cyclohexyl-ethyl)-(S*)-amino)-cyclohexan-1-(S*)-yl)-sulfanyl)-acetyl]-mutilin: 8.35, 8.65 (2xb, 2H,NH₂ ⁺), AB-system (v_(A) = 3.38, v_(B) = 3.28, H₂₂, J = 14.5 Hz), 3.25(b, 1H, NCHCH₂), 3.15 (b, 1H, SCH), 1.2 (d, 3H, CH₃CH, 4.4 Hz) 26a

C514-O-[((3-((S)-Phenylethyl)-(R*)-amino)-cyclopentan-1-(S*)-yl)-sulfanyl)-acetyl]-mutilin:9.25,9.35, 9.55 (3xb, 2H, (NH₂)⁺), 7.4, 7.6 (2xm, 5H,arom.H), AB-system(v_(A) = 3.22, v_(B) = 3.32, H₂₂,J = 15 Hz), 3.05, 3.15 (2xb, 2H, SCH,NCH), 1.52(d, 3H, C₆H₅CHCH₃N, J = 6.5 Hz), MS m/e:582 (MH⁺) 26b14-O-[((3-((S)-Phenylethyl)-(S*)-amino)-cyclopentan-1-(S*)-yl)-sulfanyl)-acetyl]-mutilin: 9.25, 9.9.7 (2xb, 2H,(NH₂)⁺), 7.4, 7.6 (2xm, 5H, arom.H), 3.22 (m, 2H, H₂₂), 4.3 (b, 1H,C₆H₅CHN), 1.52 (d, 3H, C₆H₅CHCH₃N, J = 6.5 Hz), MS m/e: 582 (MH⁺) 26c14-O-[((3-((R)-Phenylethyl)-(R*)-amino)-cyclopentan-1-(S*)-yl)-sulfanyl)-acetyl]-mutilin: 9.25, 9.35, 9.55 (3xb,2H, (NH₂)⁺), 7.4, 7.6 (2xm, 5H, arom.H), 3.22 (m, 2H, H₂₂), 4.3 (b, 1H,C₆H₅CHN), 3.05, 3.2 (2xb, 2H, SCH, NCH), 1.52 (d, 3H, C₆H₅CHCH₃N, J =6.5 Hz), MS m/e: 582 (MH⁺) 26d 14-O-[((3-((R)-Phenylethyl)-(S*)-amino)-cyclohexan-1-(S*)-yl)-sulfanyl)-acetyl]-mutilin: 9.3, 9.75 (2xb, 2H,(NH₂)⁺), 7.4, 7.6 (2xm, 5H, arom.H), AB-system (v_(A) = 3.18, v_(B) =3.30, H₂₂, J = 14.5 Hz), 4.3 (b, 1H, C₆H₅CHN), 1.58 (d, 3H, C₆H₅CHCH₃N,J = 6.5 Hz), MS m/e: 582 (MH⁺). 27a

C614-O-[(3-(R*)-((S)-Phenylethyl)amino)-cyclohexan-1-(R*)-yl)-sulfanyl)-acetyl]-mutilin:8.95,9.3 (2xb, 2H, (NH₂)⁺), 7.4, 7.6 (2xm, 5H, arom.H), 3.15 (s, 2H, H₂₂),4.5 (b, 1H, C₆H₅CHN), 3.35 (m,1H, NCH), 2.9 (b, 1H, SCH), 1.55(d,3HC₆H₅CHCH₃N, J = 6.5 Hz) 27b 14-O-[(3-(S*)-((S)-Phenylethyl)amino)-cyclohexan-1-(R*)-yl)-sulfanyl)-acetyl]-mutilin: 8.8, 9.0 (2xb, 2H,(NH₂)⁺), 7.4, 7.6 (2xm, 5H, arom.H), AB-system (v_(A) = 3.35, v_(B) =3.4, 2H, H₂₂, J = 14 Hz), 4.45 (b, 1H, C₆H₅CHN), 3.18 (b, 2H, SCH, NCH),1.55 (d, 3H, C₆H₅CHCH₃N, J = 6.5 Hz) 27c14-O-[(3-(S*)-((R)-Phenylethyl)amino)-cyclohexan-1-(R*)-yl)-sulfanyl)-acetyl]-mutilin: 9.0, 9.5 (2xb, 2H,(NH₂)⁺), 7.4, 7.6 (2xm, 5H, arom.H), 3.29 (s, 2H, H₂₂), 4.45 (b, 1H,C₆H₅CHN), 2.65 (b, 2H, SCH, NCH), 1.55 (d, 3H, C₆H₅CHCH₃N, J = 6.5 Hz)27d 14-O-[(3-(R*)-((R)-Phenylethyl)amino)-cyclohexan-1-(R*)-yl)-sulfanyl)-acetyl]-mutilin: 8.95, 9.45 (2xb, 2H,(NH₂)⁺), 7.4, 7.6 (2xm, 5H, arom. H), 3.29 (s, 2H, H₂₂), 4.55 (b, 1H,C₆H₅CHN), 2.9 (b, 1H, SCH), 1.55 (d, 3H, C₆H₅CHCH₃N, J = 6.5 Hz) 27e14-O-[(3-(R*)-((R)-Phenylethyl)amino)-cyclohexan-1-(S*)-yl)-sulfanyl)-acetyl]-mutilin: 9.15, 9.45 (2xb, 2H,(NH₂)⁺), 7.4, 7.6 (2xm, 5H, arom.H), AB-system (v_(A) = 3.38, v_(B) =3.42, H₂₂, J = 14 Hz), 4.55 (b, 1H, C₆H₅CHN), 2.6 (b, 2H, NCH, SCH),1.55 (d, 3HC₆H₅CHCH₃N, J = 6.5 Hz) 27f14-O-[(3-(S*)-((R)-Phenylethyl)amino)-cyclohexan-1-(S*)-yl)-sulfanyl)-acetyl]-mutilin: 9.0, 9.35 (2xb, 2H,(NH₂)⁺), 7.4, 7.6 (2xm, 5H, arom.H), AB-system (v_(A) = 3.12, v_(B) =3.25, H₂₂, J = 15 Hz), 4.5 (b, 1H, C₆H₅CHN), 2.9 (b, 1H, SCH), 1.55 (d,3HC₆H₅CHCH₃N, J = 6.5 Hz) 28

C514-O-{[3(R/S)-(1H-Benzoimidazol-2-ylmethylamino)-cyclopent-1(R/S)-ylsulfanyl]-acetyl}-mutilin:9.9 (b, 2H, (NH₂)⁺),7.65, 7.3 (2xm, 4H, arom.H), 3.7, 3.85(2xm, 1H,NCH), 3.45 (d, 2H, NCH₂, J = 5.9 Hz),3.3 (m, 2H, H₂₂), 3.45, 3.15 (2xm,1H, SCH), MSm/e: 608 (MH⁺) 29a

C514-O-{[(3(S*)-Dimethylamino-cyclopent-1(R*)-yl)-sulfanyl]-acetyl}-mutilin +1(S*)3(R*)Diastereomer: 10.02 (b, 1H, NH⁺), 3.48 (m, 1H,NCH)), 3.2 (m,1H, SCH), 2.7 (s, 6H, N(CH₃)₂), MSm/e: 506 (M⁺) 29b14-O-{[(3(S*)-Dimethylamino-cyclopent-1(S*)-yl)-sulfanyl]-acetyl}-mutilin + 1(R*)3(R*) Diastereomer: 10.2 (b, 1H,NH⁺), 3.65 (m, 1H, NCH)), 3.25 (m, 1H, SCH), 2.7 (s, 6H, N(CH₃)₂), MSm/e: 506 (M⁺) 30a

C514-O-{[(3(S*)-Diethylamino-cyclopent-1(R*)-yl)-sulfanyl]-acetyl}-mutilin +1(S*) 3(R*)Diastereomer): 10.0 (b, 1H, NH⁺), 3.6 (b,1H, NCH)), 3.02-3.15(2xb, 4H, NCH₂CH₃), 1.15 (bt,3H, CH₃CH₂). MS m/e: 534 (M⁺) 30b14-O-{[(3(S*)-Diethylamino-cyclopent-1(S*)-yl)-sulfanyl]-acetyl}-mutilin + 1(R*) 3(R*)- Diastereomer: 10.3 (b, 1H,NH⁺), 3.71 (m, 1H, NCH)), AB-system (v_(A) = 3.28, v_(B) = 3.35, H₂₂, J= 14.5 Hz), 3.05-3.15 (2xb, 4H, NCH₂CH₃), 1.15 (t, 3H, CH₃CH₂, J = 4.4Hz). MS m/e: 534 (M⁺) 31

C714-O-[(3-(R/S)-Diethylamino-cycloheptane-1(R/S)-yl)-sulfanylacetyl]-mutilin:10.05 (b, 1H,N(C₂H₅)₂H⁺), 3.3-3.5 (m, 3H, H₁₁, H₂₂), 3.05, 3.12,3.2(3xb, 5H, NCH₂CH₃, NCH), 1.95 (b, 1H, SCH),1.24, 1.28 (2xt, 6H, NCH₂CH₃,J = 8.2 Hz) 32

C514-O-{[(3-(R/S)-Cyclopropylamino-cyclopent-1(R/S)-yl)-sulfanyl]-acetyl}-mutilin:9.1(b, 2H, (NH₂)⁺), 3.15, 3.55, 3.65 (3xm, 2H, 2xNCH),3.3 (m, 2H, H₂₂),2.65 (b, 1H, SCH), 0.7, 0.9 (2xm,4H, Cyclopropyl-H). 33a

C614-O-{[(3-(S)-Cyclopropylamino-cyclohexan-1(R)-yl)-sulfanyl]-acetyl}-mutilin +1S3R-Diastereomer: 9.0 (b, 2H, (NH₂)⁺), 3.33 (m, 2H, H₂₂),2.68, 2.75,3.08 (3xm, 3H, 2xNCH, SCH), 0.73,0.85 (2xm, 4H, Cyclopropyl-H), MSm/e:532 (MH⁺). 33b 14-O-{[(3-(R)-Cyclopropylamino-cyclohexan-1(R)-yl)-sulfanyl]-acetyl}-mutilin + 1S3S- Diastereomer: 8.9 (b, 2H,(NH₂)⁺), 3.2-3.35 (m, 4H, H₂₂, NCH, SCH), 2.65 (m, 1H, NCH), 0.74, 0.83(2xm, 4H, Cyclopropyl-H), MS m/e: 532 (MH⁺). 34a

C614-O-[((3-(R*)-(Morpholin-4-yl)-cyclohexan-1-(S*)-yl)-sulfanyl)-acetyl]-mutilin:10.5 (b, 1H,NH⁺), 3.3-3.45 (m, 4H, H₂₂, NCH, SCH), 3.75, 3.95(2xb, 4H,OCH₂), 3.05, 3.25 (2xb, 4H, NCH₂) 34b14-O-[((3-(R*)-(Morpholin-4-yl)-cyclohexan-1-(R*)-yl)-sulfanyl)-acetyl]-mutilin: 10.5 (b, 1H, NH⁺), AB-system (v_(A)= 3.35, v_(B) = 3.4, 2H, H₂₂, J = 14 Hz) 3.75, 3.95 (2xb, 4H, OCH₂),3.15, 3.25 (2xb, 4H, NCH₂), 3.05 (b, 1H, NCH) 35

C514-O-{[3(R/S)-(1H-Imidazol-2-ylamino)-cyclopent-1(R/S)-ylsulfanyl]-acetyl}-mutilin:12.0(s, 2H, imidazole-NH), 8.1 (m, 2H, (NH₂)⁺),6.9 (s, 2H, imidazole-H),3.85, 4.0 (2xm, 1H, NCH),3.3 (m, 2H, H₂₂), 3.1 (m, 1H, SCH), MS m/e:544(MH⁺) 36

C514-O-{[3(R/S)-(1H-Benzoimidazol-2-ylamino)-cyclopent-1(R/S)-ylsulfanyl]-acetyl}-mutilin:12.6(b, 2H, (NH₂)⁺), 9.1 (d, 1H, NH, J = 7.5 Hz), 7.4,7.2 (2xm, 4H, arom.H),4.1 (m, 1H, NCH), 3.3 (m, 2H,H₂₂), 2.6 (m, 1H, SCH), MS m/e: 594 (MH⁺)In TABLE 1 in column “EX” the Example number is indicated. in allcompounds listed the subsituent “R_(EX)” is in the 3-position of thecorresponding cycloalkyl, “CYC” means cycloalkylene and in column “CYC”there is indicated the ring member number of the correspondingcycloalkylene and optionally cycloalkyl substitution (C5, C6 or C7,respectively, means, beside R_(EX) substitution, unsubstitutedcyclopentylene, cyclohexylene or cylooheptylene, respectively), allcompounds are obtained in free form and in the form of a hydrochloridesalt, in column “DATA” H¹-NMR data is indicated (determined in d₆-DMSOat 400 or 500 MHz) and optionally mass spectroscopy data (MS-ESI); andall data indicated is data obtained from the hydrochloride salt of thecorresponding compound of formula EX, except for Example 11 and 12 wheredata is obtained from the free form, the ¹H-NMR-data of the tricylicmutilin are indicated in Example 1a. In the other Examples only data ofthe C-14 side chain is indicated, unless there is substantial changeconcerning data of the mutilin ring.

1-14. (canceled)
 15. A compound comprising: a chemical formula selectedfrom the group consisting of: 14-O-[((Mono- ordialkylamino)-cycloalkylsulfanyl- or -cycloalkyl-oxy)-acetyl,-thioacetyl or -imino-oxy]-mutilins; 14-O-[((Cycloalkyl- orheterocyclylamino)-cycloalkylsulfanyl- or -cycloalkyl-oxy)-acetyl,-thioaceyl or -imino-oxy]-mutilins;14-O-[((Heterocyc-N-yl-cycloalkyl)-sulfanyl- or -oxy)-acetyl,-thioacetyl or -imino-oxy]-mutilins; 14-O-[(((Mono- ordialkylamino)-cycloalkyl)-alkylsulfanyl- or -alkyl-oxy)-acetyl,-thioacetyl or -imino-oxy]-mutilins; 14-O-[(((Cycloalkyl- orheterocyclylamino)-cycloalkyl)-alkylsulfanyl- or -alkyl-oxy)-acetyl,-thioacetyl or -imino-oxy]-mutilins; and14-O-[((Heterocyc-N-yl-cycloalkyl)-alkylsulfanyl- or -alkyl-oxy)-acetyl,-thioacetyl or -imino-oxy]-mutilins.
 16. The compound according to claim15, wherein the chemical formula is selected from the group consistingof: 14-O-[((Mono- or dialkylamino)-cycloalkylsulfanyl- or-cycloalkyl-oxy)-acetyl]-mutilins; 14-O-[((Cycloalkyl- orheterocyclylamino)-cycloalkylsulfanyl- or-cycloalkyl-oxy)-acetyl]-mutilins;14-O-[((Heterocyc-N-yl-cycloalkyl)-sulfanyl- or -oxy)-acetyl]-mutilins;14-O-[(((Mono- or dialkylamino)-cycloalkyl)-alkylsulfanyl- or-alkyl-oxy)-acetyl]-mutilins; 14-O-[(((Cycloalkyl- orheterocyclylamino)-cycloalkyl)-alkylsulfanyl- or-alkyl-oxy)-acetyl]-mutilins; and14-O-[((Heterocyc-N-yl-cycloalkyl)-alkylsulfanyl- or-alkyl-oxy)-acetyl]-mutilins.
 17. The compound according to claim 16,wherein the chemical formula is selected from the group consisting of:14-O-[((Mono- or dialkylamino)-cycloalkylsulfanyl- or-cycloalkyl-oxy)-acetyl]-mutilins; 14-O-[((Cycloalkyl- orheterocyclylamino)-cycloalkylsulfanyl- or-cycloalkyl-oxy)-acetyl]-mutilins; and14-O-[((Heterocyc-N-yl-cycloalkyl)-sulfanyl- or -oxy)-acetyl]-mutilins.18. The compound according to claim 17, wherein the chemical formula isselected from the group consisting of: 14-O-[((Mono- ordialkylamino)-cycloalkylsulfanyl)-acetyl]-mutilin; 14-O-[((Cycloalkyl-or heterocyclylamino)-cycloalkylsulfanyl)-acetyl]-mutilin; and14-O-[((Heterocyc-N-yl-cycloalkyl)-sulfanyl)-acetyl]-mutilin.
 19. Thecompound according to claim 15, wherein the chemical formula ischaracterized by having general structural formula I:

wherein: R is hydrogen or (C₁₋₈)alkyl; R₁ is one of the following: acycloalkyl selected from the group consisting of a (C₃₋₁₂)cycloalkyl,(C₄₋₈)cycloalkyl, and (C₅₋₇)cycloalkyl; an unsubstituted (C₁₋₈)alkyl;and a (C₁₋₈)alkyl substituted by one or more of the following: one ortwo hydroxy groups; a halogen; an alkyloxycarbonyl or(C₁₋₆)alkyloxycarbony; an alkylaminocarbonyl or(C₁₋₄)alkylaminocarbonyl; a (C₃₋₈)cycloalkyl or cyclohexyl; a(C₆₋₁₈)aryl or phenyl; or a heterocyclyl including a heterocyclic groupcomprising at least one of the following: 3 to 7 ring members;heteroatoms selected from the group consisting of N, O and S; or aheterocyclyl anellated with another ring system; X is sulphur, oxygen orNR₁₀, wherein R₁₀ is hydrogen or (C₁₋₈)alkyl; Y is sulphur or oxygen; R₂is hydrogen or one or more substituents that are conventional in organicchemistry; R₄ and R₅ independently of each other are hydrogen or(C₁₋₈)alkyl; R₃ and R₃′ are independently hydrogen, deuterium, orhalogen; R₆, R₇ and R₈ independently of each other are hydrogen, halogenor deuterium; m is a number selected from 0 to 4; n is a number selectedfrom 0 to 10; and p is a number selected from 0 to 10; with the provisothat n plus p are at least
 1. 20. The compound of claim 19, wherein R₂is hydrogen or (C₁₋₄)alkyl; R₃ is hydrogen; R₃′ is hydrogen; R₄ ishydrogen; R₅ is hydrogen; R₆ is hydrogen; R₇ is hydrogen; X is oxygen; Yis sulphur; m is a number selected from 0 to 4; n is a number selectedfrom 0 to 8; and p is a number selected from 0 to 8; with the provisothat n plus p are at least
 2. 21. The compound according to claim 15,wherein the chemical formula is characterized by having generalstructural formula I_(p):

wherein: R is hydrogen or (C₁₋₈)alkyl; R₁ is one of the following: acycloalkyl selected from the group consisting of a (C₃₋₁₂)cycloalkyl,(C₄₋₈)cycloalkyl, and (C₅₋₇)cycloalkyl; an unsubstituted (C₁₋₈)alkyl;and a (C₁₋₈)alkyl substituted by one or more of the following: one ortwo hydroxy groups; a halogen; an alkyloxycarbonyl or(C₁₋₆)alkyloxycarbony; an alkylaminocarbonyl or(C₁₋₄)alkylaminocarbonyl; a (C₃₋₈)cycloalkyl or cyclohexyl; a(C₆₋₁₈)aryl or phenyl; or a heterocyclyl including a heterocyclic groupcomprising at least one of the following: 3 to 7 ring members;heteroatoms selected from the group consisting of N, O and S; or aheterocyclyl anellated with another ring system; R₂ is hydrogen or(C₁₋₄)alkyl; and q is a number selected from 0, 1 and
 2. 22. Thecompound according to claim 15, wherein the chemical formula is selectedfrom the group consisting of:14-O-[(3-Diethylamino-cyclohexan-1-yl)-sulfanylacetyl]-mutilin;14-O-{[(3-Methylamino-cyclopent-1-yl)-sulfanyl]-acetyl}-mutilin;14-O-{[(3-Ethylamino-cyclopent-1-yl)-sulfanyl]-acetyl}-mutilin;14-O-{[(3-Ethylamino-1-methyl-cyclopent-1-yl)-sulfanyl]-acetyl}-mutilin;14-O-{[(3-Ethylamino-2-methyl-cyclopent-1-yl)-sulfanyl]-acetyl}-mutilin;14-O-{[3-Ethylamino-cyclohexanylsulfanyl]-acetyl}-mutilin;14-O-{[3-(sec-Butylamino)-cyclopent-1-ylsulfanyl]-acetyl}-mutilin;14-O-[((3-(sec-Butylamino)-cyclohexan-1-yl)-sulfanyl)-acetyl]-mutilin;14-O-[((1-(sec-Butylamino)-cycloheptan-3-yl)-sulfanyl)-acetyl]-mutilin;14-O-{[3-(2,2,2-Trifluoro-ethylamino)-cyclopent-1-ylsulfanyl]-acetyl}-mutilin;14-O-{[3-(2,2,2-Trifluoro-ethylamino)-cyclohexan-1-ylsulfanyl]-acetyl}-mutilin;14-O-{[3-(2,2-Difluoro-ethylamino)-cyclohexan-1-ylsulfanyl]-acetyl}-mutilin;14-O-{[(3-(2-Hydroxy-ethylamino)-cyclopent-1-yl)-sulfanyl]-acetyl}-mutilin;14-O-{[3-(2-Hydroxy-propylamino)-cyclopent-1-ylsulfanyl]-acetyl}-mutilin;14-O-[((3-(1-Isopropyl-2-hydroxy-ethylamino)-cyclopent-1-yl)-sulfanyl)-acetyl]-mutilin;14-O-[((3-(1-Isopropyl-2-hydroxy-ethylamino)-cyclohexan-1-yl)-sulfanyl)-acetyl]-mutilin;14-O-{[3-(2-Hydroxy-1-hydroxymethyl-1-methyl-ethylamino)-cyclopent-1-ylsulfanyl]-acetyl}-mutilin;14-O-{[3-(2-Hydroxy-1,1-bis-hydroxymethyl-ethylamino)-cyclopent-1-ylsulfanyl]-acetyl}-mutilin;14-O-[((3-(Methoxycarbonyl-methylamino)-cyclopent-1-yl)-sulfanyl)-acetyl]-mutilin;14-O-[((3-(Ethoxycarbonyl-methylamino)-cyclopent-1-yl)-sulfanyl)-acetyl]-mutilin;14-O-[(((3-(Isopropoxycarbonyl-methylamino)-cyclopent-1-yl)-sulfanyl)-acetyl]-mutilin;14-O-{[3-(Methoxypropionyl-2-amino)-cyclopent-1-yl-sulfanyl]-acetyl}-mutilin;14-O-{[3-(Isopropoxypropionyl-2-amino)-cyclopent-1-yl-sulfanyl]-acetyl}-mutilin;14-O-{[(3-Methylcarbamoylmethylamino-cyclopent-1-yl)-sulfanyl]-acetyl}-mutilin;14O-[(((3-(1-Cyclohexylethyl)-amino)-cyclohexan-1-yl)-sulfanyl)-acetyl]-mutilin;14-O-[(((3-(Phenylethyl)-amino)-cyclopentan-1-yl)-sulfanyl)-acetyl]-mutilin;14-O-[(((3-(Phenylethyl)-amino)-cyclohexan-1-yl)-sulfanyl)-acetyl]-mutilin;14-O-{[3-(1H-Benzoimidazol-2-ylmethylamino)-cyclopent-1-ylsulfanyl]-acetyl}-mutilin;14-O-{[(3-Dimethylamino-cyclopent-1-yl)-sulfanyl]-acetyl}-mutilin;14-O-{[(3-Diethylamino-cyclopent-1)-yl)-sulfanyl]-acetyl}-mutilin;14-O-[((3-Diethylamino-cycloheptan-1-yl)-sulfanyl)-acetyl]-mutilin;14-O-{[(3-Cyclopropylamino-cyclopent-1-yl)-sulfanyl]-acetyl}-mutilin;14-O-{[(3-Cyclopropylamino-cyclohexan-1-yl)-sulfanyl]-acetyl}-mutilin;14-O-[((3-(Morpholin-4-yl)-cyclohexan-1-yl)-sulfanyl)-acetyl]-mutilin;14-O-{[(3-(1H-Imidazol-2-ylamino)-cyclopent-1-yl)-sulfanyl]-acetyl}-mutilin;and14-O-{[(3-(1H-Benzoimidazol-2-ylamino)-cyclopent-1-yl)-sulfanyl]-acetyl}-mutilin.23. A compound as in claim of claim 15, in the form of a salt and/orsolvate.
 24. A compound according to claim 15, suitable for use as apharmaceutical.
 25. A method of treatment of diseases mediated bymicrobes which comprises: administering to a subject in need of suchtreatment an effective amount of a compound with a chemical formulaselected from the group consisting of: 14-O-[((Mono- ordialkylamino)-cycloalkylsulfanyl- or -cycloalkyl-oxy)-acetyl,-thioacetyl or -imino-oxy]-mutilins; 14-O-[((Cycloalkyl- orheterocyclylamino)-cycloalkylsulfanyl- or -cycloalkyl-oxy)-acetyl,-thioacetyl or -imino-oxy]-mutilins;14-O-[((Heterocyc-N-yl-cycloalkyl)-sulfanyl- or -oxy)-acetyl,-thioacetyl or -imino-oxy]-mutilins; 14-O-[(((Mono- ordialkylamino)-cycloalkyl)-alkylsulfanyl- or -alkyl-oxy)-acetyl,-thioacetyl or -imino-oxy]-mutilins; 14-O-[(((Cycloalkyl- orheterocyclylamino)-cycloalkyl)-alkylsulfanyl- or -alkyl-oxy)-acetyl,-thioacetyl or -imino-oxy]-mutilins; and14-O-[((Heterocyc-N-yl-cycloalkyl)-alkylsulfanyl- or -alkyl-oxy)-acetyl,-thioacetyl or -imino-oxy]-mutilins.
 26. A method of preparing amedicament for the treatment of diseases mediated by microbes, saidmethod comprising: preparing a medicament having compound with achemical formula selected from the group consisting of: 14-O-[((Mono- ordialkylamino)-cycloalkylsulfanyl- or -cycloalkyl-oxy)-acetyl,-thioacetyl or -imino-oxy]-mutilins; 14-O-[((Cycloalkyl- orheterocyclylamino)-cycloalkylsulfanyl- or -cycloalkyl-oxy)-acetyl,-thioaceyl or -imino-oxy]-mutilins;14-O-[((Heterocyc-N-yl-cycloalkyl)-sulfanyl- or -oxy)-acetyl,-thioacetyl or -imino-oxy]-mutilins; 14-O-[(((Mono- ordialkylamino)-cycloalkyl)-alkylsulfanyl- or -alkyl-oxy)-acetyl,-thioacetyl or -imino-oxy]-mutilins; 14-O-[(((Cycloalkyl- orheterocyclylamino)-cycloalkyl)-alkylsulfanyl- or -alkyl-oxy)-acetyl,-thioacetyl or -imino-oxy]-mutilins; and14-O-[((Heterocyc-N-yl-cycloalkyl)-alkylsulfanyl- or -alkyl-oxy)-acetyl,-thioacetyl or -imino-oxy]-mutilins.
 27. A pharmaceutical compositioncomprising: a compound in association with at least one pharmaceuticalexcipient, said compound having a chemical formula selected from thegroup consisting of: 14-O-[((Mono- or dialkylamino)-cycloalkylsulfanyl-or -cycloalkyl-oxy)-acetyl, -thioacetyl or -imino-oxy]-mutilins;14-O-[((Cycloalkyl- or heterocyclylamino)-cycloalkylsulfanyl- or-cycloalkyl-oxy)-acetyl, -thioaceyl or -imino-oxy]-mutilins;14-O-[((Heterocyc-N-yl-cycloalkyl)-sulfanyl- or -oxy)-acetyl,-thioacetyl or -imino-oxy]-mutilins; 14-O-[(((Mono- ordialkylamino)-cycloalkyl)-alkylsulfanyl- or -alkyl-oxy)-acetyl,-thioacetyl or -imino-oxy]-mutilins; 14-O-[(((Cycloalkyl- orheterocyclylamino)-cycloalkyl)-alkylsulfanyl- or -alkyl-oxy)-acetyl,-thioacetyl or -imino-oxy]-mutilins; and14-O-[((Heterocyc-N-yl-cycloalkyl)-alkylsulfanyl- or -alkyl-oxy)-acetyl,-thioacetyl or -imino-oxy]-mutilins.
 28. A pharmaceutical compositionaccording to claim 27, further comprising another pharmaceuticallyactive agent.